The activation of the endothelium by inflammatory triggers initiates a cascade of signaling pathways with the aim of eliminating the danger signal and resolving the inflammatory response, to finally return the endothelium to its basal state1. Failure to do so results in excessive vascular inflammation leading to tissue damage in acute situations and cardiovascular diseases such as atherosclerosis and fibrosis in chronic situations. Although broad immunosuppressive strategies, such as blocking tumor necrosis factor alpha (α), interleukin 1beta (IL-1β) or interleukin 6 (IL-6) with neutralizing antibodies, have shown promising results in clinical trials to reduce the Vascular inflammation2, its considerable side effects and limited efficacy indicate the need for more specific alternative targets, potentially downstream of these cytokines, and preferably specific for the endothelium.
Mitochondria are multifaceted organelles best known for their role in cellular energy production through oxidative phosphorylation and in apoptosis through the release of cytochrome c. In addition to energy homeostasis, the role of mitochondria in regulating the onset and results of inflammation is increasingly appreciated3. A classic example is the production of reactive oxygen species (ROS) from the respiratory chain. Once thought to be purely pathogenic, it is now appreciated that low or physiological ROS levels play normative roles in pro-inflammatory and pro-resolution signaling pathways, while excessive ROS can lead to chronic activation of pro-inflammatory mechanisms that cause tissue damage 4. It is also known that mitochondria are a proximal site for the activation of the response to interferon (IR) through the localization of MAVS5 or the activation of the inflammasome through the extrusion of cardiolipin6. Mitochondrial DNA leakage can also trigger IR or inflammatory cell death through the c-GAS / STING7 pathway. In addition, metabolites of the Krebs cycle, such as succinate and itaconate, are increasingly recognized as modulators of inflammation; for example, by regulating the NLRP3 inflammasome and the IR8,9 pathway. Although mitochondrial dysfunction is widely implicated in the pathogenesis of cardiovascular disease, the specific role of mitochondria in endothelial health and dysfunction has received relatively little attention. In particular, how endothelial mitochondria respond to and modulate an inflammatory response is not well understood.
Previously, our laboratory reported on a preponderance of small open reading frame (sORF) encoded peptides, defined as proteins of less than 100 residues that are located in the mitochondria (mito-SEP) 10. These peptides have functions in various processes in mitochondria, including electron transport, lipid metabolism, and calcium homeostasis. We asked the question whether mito-SEPs might play a hitherto little appreciated role in regulating inflammation. For example, Fitzgerald and his colleagues recently identified a mitochondrial peptide Mm47 that is required for the activation of the inflammasome NLRP311.
In this study, we performed proteogenomic screening to find mito-SEP in primary human aortic endothelial cells (HAEC) that can promote the resolution of inflammation. We report the discovery of the modulator of cytochrome C oxidase during inflammation (MOCCI), a mito-SEP encoded by C15ORF48. Together with miR-147b in the 3 'untranslated region (UTR) of C15ORF48, MOCCI replaces its paralog NDUFA4 in Complex IV (CIV). This dampens the activity of the CIV and protects the host tissue against excessive immune pathology by reducing cell death and cytokine production. Additionally, miR-147b exerts powerful antiviral effects by enhancing IR through the RIG-I / MDA5 pathway. Together, the coding and noncoding functions of C15ORF48 synergize to protect the host during infection, illustrating how small peptides coordinate with their coding transcripts for maximum biological impact.